HtrA2 deficiency causes mitochondrial uncoupling through the F1F0-ATP synthase and consequent ATP depletion

• Published in: Cell death & disease Vol. 3; no. 6; p. e335
• Main Authors: Plun-Favreau, H, Burchell, V S, Holmström, K M, Yao, Z, Deas, E, Cain, K, Fedele, V, Moisoi, N, Campanella, M, Miguel Martins, L, Wood, N W, Gourine, A V, Abramov, A Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2012; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/378/1689/364; 631/45/607/468; 631/80/304; 631/80/642/333; Adenosine Triphosphate - metabolism; Amino Acid Sequence; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Respiration; High-Temperature Requirement A Serine Peptidase 2; Immunology; Life Sciences; Membrane Potential, Mitochondrial - physiology; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Sequence Data; Original; original-article; Oxidative Phosphorylation; Proton-Translocating ATPases - metabolism; Reactive Oxygen Species - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; uncoupling; ATP synthase; HtrA2; mitochondria
• ISSN: 2041-4889
• DOI: 10.1038/cddis.2012.77

Loss of the mitochondrial protease HtrA2 (Omi) in mice leads to mitochondrial dysfunction, neurodegeneration and premature death, but the mechanism underlying this pathology remains unclear. Using primary cultures from wild-type and HtrA2-knockout mice, we find that HtrA2 deficiency significantly reduces mitochondrial membrane potential in a range of cell types. This depolarisation was found to result from mitochondrial uncoupling, as mitochondrial respiration was increased in HtrA2-deficient cells and respiratory control ratio was dramatically reduced. HtrA2-knockout cells exhibit increased proton translocation through the ATP synthase, in combination with decreased ATP production and truncation of the F1 α -subunit, suggesting the ATP synthase as the source of the proton leak. Uncoupling in the HtrA2-deficient mice is accompanied by altered breathing pattern and, on a cellular level, ATP depletion and vulnerability to chemical ischaemia. We propose that this vulnerability may ultimately cause the neurodegeneration observed in these mice.